An age-dependent association of mannose-binding lectin-2 genetic variants on HIV1–related disease...

An age-dependent association of mannose-binding lectin-2genetic variants on HIV-1-related disease in children

Kumud K. Singh, PhDa, Alexis Lieser, MDb, Ping K. Ruan, PhDc, Terry Fenton, EdDc, andStephen A. Spector, MDa

aDepartment of Pediatrics, Division of Infectious Diseases, University of California, San Diego, LaJolla, CaliforniabUniversity of California Irvine Medical Center, Orange, CaliforniacCenter for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Mass

AbstractBackground—Mannose-binding lectin (MBL) is part of the lectin pathway of complementactivation against various pathogens; however, its role in innate immune responses against HIV-1infection in children is unknown.

Objective—This study evaluated the effects of mannose-binding lectin-2 (MBL2) alleles onHIV-1 disease progression and central nervous system (CNS) impairment in children.

Methods—A cohort of 1037 HIV-1-infected children enrolled in Pediatrics AIDS Clinical TrialGroup protocols P152 and P300 before the availability of effective antiretroviral therapy wasgenotyped for MBL2 and evaluated for disease progression.

Results—Children with the homozygous variant MBL2-O/O genotype were more likely toexperience rapid disease progression and CNS impairment than those with the wild-type AAgenotype. The effects were predominantly observed in children younger than 2 years. Inunadjusted Cox proportional hazards models, children younger than 2 years with MBL2-O/Oexperienced more rapid disease progression (O/O vs AA: relative hazard [RH], 1.54; 95% CI,1.07-2.22; P = .02; O/O vs A/O: RH, 2.28; 95% CI, 1.09-4.79; P = .029). Similarly, children withMBL2-O/O were more likely to experience rapid progression to CNS impairment (O/O vs A/A:RH, 2.78; 95% CI, 1.06-2.69, P = .027; O/O vs A/O: RH, 1.69; 95% CI, 1.07-7.21; P = .035). Theeffects remained significant after adjustment for CD4+ lymphocyte count, plasma HIV-1 RNA,and other genotypes.

Conclusions—MBL2-O/O genotypes, which result in lower expression of MBL, are associatedwith more rapid HIV-1-related disease progression, including CNS impairment, predominantly inchildren younger than 2 years. These data suggest that MBL2 variants are associated with alteredHIV-1 disease progression, particularly in young children.

© 2008 American Academy of Allergy, Asthma & ImmunologyReprint requests: Stephen A. Spector, MD, Department of Pediatrics, University of California, San Diego, 9500 Gilman Dr, La Jolla,CA 92093-0672. [email protected]; or Kumud K. Singh, PhD, Department of Pediatrics, University of California, San Diego, 9500Gilman Dr, La Jolla, CA 92093-0672. [email protected] of potential conflict of interest: The authors have declared that they have no conflict of interest.Presented in part at the XIVth Conference on Retroviruses and Opportunistic Infections, Los Angeles, Calif, February 25-28, 2007.Clinical implications: HIV-1-infected children who have MBL2 genetic variants that result in lower MBL levels have a significantlygreater risk for HIV-related complications, including cognitive impairment, particularly young children.

NIH Public AccessAuthor ManuscriptJ Allergy Clin Immunol. Author manuscript; available in PMC 2009 September 22.

Published in final edited form as:J Allergy Clin Immunol. 2008 July ; 122(1): 173–180.e2. doi:10.1016/j.jaci.2008.05.025.

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KeywordsMannose binding lectin-2; polymorphisms; HIV-1 disease; central nervous system impairment;children

Innate immunity comprises antigen-nonspecific defense mechanisms that a host usesimmediately or within hours after exposure to a broad spectrum of antigens to eliminatemicrobes and prevent infection. Unlike adaptive immunity, innate immunity is designed torecognize a few highly conserved structures present in many different microorganisms.Mannose-binding lectin protein (MBL), also called mannose-binding protein, encoded bythe mannose binding lectin-2 (MBL2) gene, is an important determinant of the innateimmune response during an infection.1-4 MBL is an acute-phase protein that is synthesizedby the liver and released into the blood-stream, where it binds to the mannose residuespresent on some bacteria, yeast, viruses, and parasites. Binding activates the lectincomplement pathway and production of C3b protein through MBL-associated serineproteases,5 which results in opsonization of pathogens, chemotaxis, activation of leukocytes,and direct killing of pathogens.

The MBL2 gene encodes 32-kd subunits that oligomerize to form 96-kd MBL structuralunits or “monomers.” The “monomers” then further associate to form high-molecular-weight MBL oligomers.4 Only the high-molecular-weight oligomer structure is capable ofactivating complement. MBL2 variants at the following nucleotide positions affect MBLlevels: 2 single nucleotide polymorphisms at promoter positions -550-G/C (H/L variant) and-221-G/C (X/Y variant), one in the 5′ untranslated region +4-C/T (P/Q variant) and 3 geneticvariants at codons 52, 54, and 57 in exon 1 at nucleotide positions 223-C/T (Arg52Cys, A/Dallele), 230-G/A (Gly54Asp, A/B allele), and 239-G/A (Gly57Glu, A/C allele), respectively.MBL2 exon 1 variants result in single amino acid changes affecting oligomerization ofMBL. Homozygous wild-type (A/A) sera contain predominantly fully functional MBL,whereas homozygous mutant sera (any combination of B, C, or D alleles) contain mostlylow-molecular-weight MBL. Sera containing heterozygous variant alleles (A/O, O = B, C, orD) contain both high-molecular-weight and low-molecular-weight MBL, with the ratiodetermined by the promoter type on the normal haplotype (A allele).

MBL deficiency was initially recognized as an opsonic defect in children with frequentunexplained infections and has been linked to increased severity and incidence ofcomplications for several inherited immunodeficiency and autoimmune diseases.6-11 MBLdeficiency has also been associated with increased HIV-1 vertical transmission.12 Recently,an age-dependent association of MBL2 variants on the susceptibility to acute respiratorytract infection and meningococcal disease was reported.8,13

The current study examined the distribution of MBL2 genotypes/haplotypes and their effecton HIV-1-related disease progression and central nervous system (CNS) impairment inchildren. We hypothesized that the presence of genetic variants of MBL2 resulting inproduction of lower or nonfunctional protein would be associated with susceptibility to HIVinfection and disease progression in children. We further hypothesized that younger childrenwith MBL2 variants would experience more rapid HIV-1 disease than older children. Ourfindings support an age-dependent association of MBL2 variants with HIV-1-related diseasein children.

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METHODSPatient populations

Two randomized, double-blind, multicenter Pediatric AIDS Clinical Trial Group (PACTG)protocols, P15214 and P30015, for seroprevalent children with symptomatic HIV-1infection were designed to compare the effects of mono-therapy with either zidovudine ordidanosine and combination therapy with zidovudine plus didanosine and to compare theeffects of zidovudine plus lamivudine with didanosine monotherapy and zidovudine plusdidanosine combination therapy, respectively. Children from both the studies, PACTG 152(n = 448) and PACTG 300 (n = 589), were screened for MBL2 exon 1, untranslated region,and promoter region polymorphisms, retrospectively.

Details of characteristics of children, eligibility criteria, study end points, diseaseprogression, and neuropsychological tests used have been described earlier.14-16 Theneuropsychological and neurodevelopmental tests administered were the Bayley Scales ofInfant Development (3-30 months old), the McCarthy Scales of Children’s Abilities (31months to 6 years old), and the Wechsler Intelligence Scale for Children: Revised (WISC-R,for 6-15 years, 11 months old) or the Wechsler Adult Intelligence Scale: Revised (WAIS-R;for >16 years of age). The Mental Developmental Index of Bayley scales, the GeneralCognitive Index of the McCarthy scales, and the full-scale IQ of the WISC-R or WAIS-Rwere used to assess cognitive function. The standard score for each test was 100, and the SDwas 16 points for the Bayley Mental Developmental Index and the McCarthy GeneralCognitive Index and 15 points for the WISC-R and WAIS-R. Children were considered tohave significant developmental delay if they had a standardized score of 70 or less or(almost equal to) 2 SDs less than the normal test score of 100. Informed consent wasobtained from study participants. This study followed the human experimentation guidelinesof the US Department of Health and Human Services and the University of California, SanDiego review board.

GenotypingMBL2 genotyping was done by means of real-time PCR with melting curve analysis(LightCycler; Roche, Indianapolis, Ind), as described earlier.17 The studied genotypesincluded 2 single nucleotide polymorphisms at promoter positions -550-G/C (H/L variant)and -221-G/C (X/Y variant), one in the 5′ untranslated region +4-C/T (P/Q variant) and 3genetic variants at codons 52, 54, and 57 in exon 1 at nucleotide positions 223-C/T(Arg52Cys, A/D allele), 230-G/A (Gly54Asp, A/B allele), and 239-G/A (Gly57Glu, A/Callele), respectively.

Statistical analysesThe primary end points for the analyses were either time to progression to first clinicalHIV-1-related disease end point or death, which constituted the progression-free survival(PFS). The disease progression included weight-growth failure, ≥2 opportunistic infections,malignancy, and/or a new abnormality of the CNS (eg, neurologic deterioration, a decreasein neurocognitive test scores, and/or brain growth failure). The CNS impairment end point, asubset of PFS, was defined as time from entry on the study to the deterioration in braingrowth, psychologic function, and/or neurologic status.14-16 Table I provides a summary ofend points by age group. The cross-tabulations of MBL2 genotypes/haplotypes by race/ethnicity and age groups were used to evaluate the genotype and allele frequencies.

Analyses of time to PFS and CNS impairment end points were performed by using Kaplan-Meier methods, and proportional hazards models were used to investigate the effects ofgenotype variants on PFS and CNS end points in univariate and multivariate analyses that

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included baseline covariates (CD4+ lymphocyte count, HIV-1 RNA, treatments, race, andsex), as well as other host genotypes previously found to alter HIV-related disease. We alsocontrolled for potential effects of treatment and treatment failure by including the change inCD4+ lymphocyte counts and plasma HIV-1 viral load during follow-up as time-varyingcovariates in the Cox proportional hazard model. Based on the hypothesis that youngerchildren with MBL2 variants might have a different experience with regard to diseaseprogression from the older children and because the median age of the children in this cohortwas 2.3 years, we performed subgroup analysis using age less than 2 years and ≥2 years asthe cutoff points to provide a balanced number of children in each age group. Theinteraction term between age and MBL2 genotype was also included in the model. Althoughthe results were as hypothesized, with the effects of genotype on outcome most evidentwithin the younger age group, the interaction term between age groups and MBL2 genotypesthat were included in the model was not statistically significant. The log-rank test was usedfor comparisons of survival curves for different genotypes. All P values are 2-sided.

RESULTSCharacteristics of children

Of the 1037 children included in this analysis, 568 (55%) were girls and 469 (45%) wereboys. The children evaluated were 60.3% non-Hispanic black, 26.1% Hispanic, and 13.6%non-Hispanic white. Ages ranged from 42 days to 18 years (<2 years, 46%; >2-5 years,26%; 5-10 years, 19%; and >10 years, 9%). The median age was 2.3 years (10th and 90thpercentiles, 0.45 and 9.5 years). Of the 1037 children, 300 (29%) were followed for less than12 months, 450 (43%) for 12 to 23 months, 197 (19%) for 24 to 35 months, and 90 (9%) formore than 35 months. A total of 226 (22%), of whom 151 (67%) were less than 2 years old,were identified as having HIV-1-related disease progression during the course of the 2studies. Characteristics of the children by 2 age groups have been summarized in Table I.

Distribution of MBL2 genotypes and haplotypesMBL2-O allele frequency was 0.27 in non-Hispanic blacks, 0.25 in Hispanics, and 0.21 innon-Hispanic whites. The prevalence of the homozygous wild type (A/A) was similar acrossall races/ethnicities (see Table E1 in the Online Repository at www.jacionline.org). Theheterozygous A/B genotype was less common and the heterozygous A/C genotype was morefrequent in the non-Hispanic blacks when compared with either Hispanics or non-Hispanicwhites (P < .001). The non-Hispanic black children had the highest C allele frequency (non-Hispanic blacks, 0.20; Hispanics, 0.07; and non-Hispanic whites, 0.05). Of note, thehomozygous mutant C/C genotype was found exclusively in the non-Hispanic blacks. Theincidence of L/L and Q/Q genotypes was more frequent in the non-Hispanic blacks. The P/Pgenotype was less common in the non-Hispanic blacks compared with Hispanics or non-Hispanic whites (P < .001). The homozygous Y/Y genotype was the most common, whereasX/X and X/Y genotypes were less frequent in all races/ethnicities. Haplotype LYPA was morecommon in non-Hispanic blacks compared with Hispanics or non-Hispanic whites, whereashaplotype HYPA was less common in non-Hispanic blacks. The distribution of MBL2variants did not differ significantly by age groups of less than 2 or more than 2 years (seeTable E2 in the Online Repository at www.jacionline.org).

Associations between disease status at study entry and MBL2 polymorphismsAt study entry, none of the MBL2 genotypes or haplotypes was significantly associated withCD4+ lymphocyte count, CD4+ lymphocyte percentage, plasma HIV-1 RNA, weight for agez score (WAZ), and sex and cognitive score (data not shown). Additionally, there weredifferences in baseline characteristics in children younger than 2 years compared with those

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in children ≥2 years (Table I). Of note, the children younger than 2 years had statisticallysignificant lower baseline WAZ scores.

MBL2 genotypes and HIV-1-related disease progression and CNS impairment in allchildren

In the whole cohort the children with the MBL2 variant genotypes showed trends towardmore rapid disease progression; the results, however, were not statistically significant (TableII). These associations followed the same trends in multivariate analyses, controlling forbaseline CD4+ lymphocytes, log10 HIV-1 RNA, treatments, race, sex, or other genotypes(CCR5-wt/Δ32, CCR5-59029, CX3CR1-249-V/I, -280-T/M, or stromal cell-derivedfactor-1). However, children with the homozygous variant MBL2-O/O genotype experiencedmore rapid CNS impairment than those with the wild-type A/A genotype (relative hazard[RH]O/O vs A/A, 1.46; 95% CI, 0.98-2.16; P = .054) and those with the heterozygous A/Ogenotype (RHO/O vs A/O, 2.24; 95% CI, 1.00-5.01; P = .045; see Table III). In addition,children with the O/O genotype showed more rapid CNS impairment than those with eitherthe A/A or A/O genotypes (RHO/O vs (A/O+A/A), 2.15; 95% CI, 1.00-4.64; P = .045). Toaddress the issue of potential bias by race/ethnicity, we controlled for race/ethnicity in amultivariate model to assess the association between disease progression/CNS end pointsand the MBL2-O/O genotype. The baseline WAZ score was also controlled for themultivariate analyses. The results showed that the significant association of the MBL2-O/Ogroup and CNS disease progression remained. No other MBL2 variants in the promoter oruntranslated regions affected HIV-1 disease in children.

MBL2 haplotypes and HIV-1-related disease progression and CNS impairment in allchildren

MBL2 haplotypes were defined as described earlier (eg, the MBL2*HYPA haplotype has-550C>G, -221C>G, 4T>C, 223T>C, 230A>G, and 239A>G variants).18 For combined A/Oand H/L genotypes, children with combined heterozygous and homozygous variants (AHOL+OLOL) showed trends toward more rapid disease progression compared with those withthe wild-type AHAH haplotype (P = .084). Furthermore, the combined AHOL+OLOLhaplotype was associated with more rapid CNS disease progression than was seen in thosewith the wild-type AHAH haplotype (P = .023). Children with the LYPA haplotype exhibiteda higher RH for CNS impairment compared with the combined group with LYPA or LXPOhaplotypes (RH, 3.39; P = .053). There were no other significant associations of haplotypeswith HIV-1 disease in children.

HIV-1 disease progression and CNS impairment for children younger than 2 versus ≥ 2years with MBL2 variants

Children younger than 2 years have immature adaptive immune responses and are known torely heavily on innate immunity. We examined the association of MBL2 variants on HIV-1-related disease for children younger than 2 and ≥2 years (Tables IV and V and Figs 1 and 2).

For the analyses of time to disease progression comparing MBL2 genotypes, childrenyounger than 2 years experienced more rapid disease progression (O/O vs A/O: RH, 2.28;95% CI, 1.09-4.79; P = .029; O/O vs A/A: RH, 1.54; 95% CI, 1.07-2.22; P = .02; O/O vs A/O+A/A: RH, 2.33; 95% CI, 1.14-4.76; P = .02; Table IV). However, no statisticallysignificant associations were observed in the analyses for children ≥2 years (O/O vs A/O:RH, 0.83; 95% CI, 0.25-2.70; P = .75; O/O vs A/A: RH, 1.05; 95% CI, 0.58-1.90; P = .87;O/O vs A/O+A/A: RH, 0.97; 95% CI, 0.30-3.07; P = .95; Table IV).

The analyses of time to CNS impairment comparing MBL2 genotypes yielded similarresults. Children younger than 2 years with O/O genotypes versus A/O genotypes

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demonstrated more rapid development of cognitive impairment (RHOO vs AO, 2.78; 95% CI,1.07-7.21; P = .035), whereas this association was again not significant for children ≥2 years(RHOO vs OA, 1.93; 95% CI, 0.41-9.01; P = .40). Similarly, for a comparison between O/Oand A/A genotypes, children younger than 2 years experienced more rapid CNS impairment(RHOO vs AA, 1.69; 95% CI, 1.06-2.69; P = .027), whereas children ≥2 years did not(RHOO vs AA, 1.33; 95% CI, 0.63-2.81; P = .45). A comparison between O/O and A/O+A/Agenotypes for the children younger than 2 years also showed a difference in CNSimpairment (O/O vs A/O+A/A: RH, 2.82; 95% CI, 1.14-7.00; P = .03). The comparison forthe children ≥2 years did not show significant effects (see Table V). The associations ofMBL2 genotypes and disease progression or CNS impairment when comparing MBL2-O/Oversus A/O, A/A, or A/O+A/A remained significant in children younger than 2 years aftercontrolling for the effects of H/L, P/Q, and X/Y alleles. Additionally, children younger than2 years with P/Q or Q/Q genotypes underwent more rapid CNS impairment compared withthose with the wild-type P/P genotype (RHP/Q vs P/P, 1.73; 95% CI, 1.03-2.91; P = .037;RHQ/Q vs P/P, 1.40; 95% CI, 1.01-1.93; P = 0.042).

DISCUSSIONTo our knowledge, this is the first comprehensive study of the distribution of MBL2 allelesand their association with HIV-1 disease in children. The homozygous variant MBL2-O/Oand L/L promoter genotype, associated with production of nonfunctional MBL, were morecommon in non-Hispanic black children compared with Hispanic and non-Hispanic whitechildren, suggesting this population might have even a higher risk of HIV-1 infection. Thelow frequency of the X/X promoter genotype, associated with low MBL expression, suggeststhat there might be a related altered susceptibility to infection in the US population,regardless of race/ethnicity. It is important to note, however, that we found no differences inthe MBL2 polymorphisms studied based on race/ethnicity on disease progression ordevelopment of CNS impairment. We found common MBL2 haplotypes in the studiedcohort; however, an earlier reported rare HXPA haplotype was also observed.19 At baseline,no effects of MBL2 polymorphisms on HIV-1 disease were observed. The hypothesis thatreduced MBL expression and function can compromise immune responses is also supportedby the data demonstrating that decreased expression of MBL on lymphocytes is associatedwith disease progression in HIV-infected adults.20

The presence of the MBL2-O/O genotype, which results in lower expression of MBL proteinand impaired innate immunity, was associated with more rapid development of HIV-1-related CNS impairment in children. Similar to earlier studies of the association of MBL2 inHIV-1-infected adults,12,20,21 we observed an overall trend toward a more rapid diseaseprogression in children with variant MBL2 genotypes; however, these results were notstatistically significant for the whole cohort. Most strikingly, we observed significantassociations between MBL2 variants and disease progression, including cognitiveimpairment in children younger than 2 years but little evidence of such an effect in olderchildren. Thus older children did not behave as did adults in their susceptibility to morefrequent infections. This finding in children older than 2 years likely reflects the highsusceptibility that children have to infectious complications associated with advanced HIV-1disease or AIDS when effective antiretroviral therapy is unavailable. Similar to our study inHIV-1-infected younger children, others have also reported age-related association of MBL2variants with acute respiratory tract infections and meningococcal disease.8,13 Our resultsdemonstrate that children younger than 2 years who have MBL2 genetic variants that resultin lower MBL levels have a significantly greater risk for disease progression and CNSimpairment. The findings in children younger than 2 years support a major role of MBL inthe immune defense of young children when the adaptive immune system is still immatureand passively acquired maternal antibodies are exhausted.22 The presence of an MBL2-O/O

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variant allele in an HIV-1-infected child suggests a higher risk of disease progression andCNS impairment and could be useful as an indicator of antiretroviral therapy in a child notreceiving treatment.

The MBL carbohydrate recognition domain has been shown to interact with the HIV-1gp120/gp41 complex,23 and dendritic cell-specific intercellular adhesion molecule-grabbingnoninte-grin-mediated transinfection of T cells is inhibited by MBL.24 The presence of theMBL2-O/O genotype, which results in lower expression of MBL protein and impaired innateimmunity, might lead to impaired viral recognition and increased infection andinflammation associated with HIV-1-related CNS impairment in children. Additionally,modulatory effects of MBL on cytokine responses have been reported.25 Enhanced TNF-αresponses were observed when PBMCs from healthy control subjects and HIV-infectedpatients were stimulated with MBL and costimulated with HIV-1 gp120 or mannan. Thusthe presence of a variant allele causing lower expression and function of MBL protein mightpotentially impair both innate and adaptive immune responses during HIV-1neuropathogenesis. Deficiency of MBL related to impaired innate and adaptive immuneresponses could be an important determinant of susceptibility to neurologic diseases. Lowerlevels of MBL have been reported previously to be associated with meningococcaldisease26,27 and Alzheimer’s disease.28

Although the role of MBL2 genetic variants in susceptibility of several diseases is wellestablished, a recent evolutionary analysis of MBL2 alleles suggested that the patterns ofMBL2 variation were compatible with neutral evolution, as opposed to negative, positive, orbalanced natural selection.29 Accordingly, the high worldwide frequencies of MBL2 allelesassociated with the production of little or no protein appear to have evolved from humanmigration and genetic drift and not survival pressure.

To our knowledge, this is the first study to examine the effect of genetic variants of MBL2on CNS impairment in HIV-1-infected children. When compared with adults, children havemore rapid HIV-1 disease progression, higher absolute numbers of CD4+ lymphocytes,higher viral loads, and more neurocognitive impairment. Thus the effect of MBL2polymorphisms on HIV-1 infection in children could be fundamentally different from thatseen in adults. Although our cohort was a seroprevalent population, the timing of infectionfor this perinatally infected cohort is known, it does not suffer from widely disparate timingand routes of infection that might be present in adult cohorts, and antiretroviral therapy waswell documented. Children in our cohort received 1 or 2 nucleoside reverse transcriptaseinhibitors (NRTIs), which were standardized for each participant. Additionally, the highnumber of clinical end points suggests that the effects of mono-NRTI or dual-NRTI therapywere limited. We also extended the analysis of the associations of MBL2 and diseaseprogression to evaluate whether the associations varied between the study treatments byincluding interaction terms in the model. However, no significant variations were observed.

In summary, our findings indicate that the presence of MBL2 variants is associated withmore rapid HIV-1 disease progression and CNS impairment in children in an age-dependentmanner, with the greatest effect observed in children younger than 2 years.

AcknowledgmentsSupported by the Pediatric AIDS Clinical Trials Group and the International Maternal Perinatal Adolescent AIDSClinical Trials (IMPAACT) Network AI068632 and AI-36214 (Virology Core, University of California, San Diego,Center for AIDS Research), and Rest Haven, San Diego, Calif.

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Abbreviations used

CNS Central nervous system

MBL Mannose-binding lectin

MBL2 Mannose binding lectin-2

NRTI Nucleoside reverse transcriptase inhibitor

PACTG Pediatric AIDS Clinical Trial Group

PFS Progression-free survival

RH Relative hazard

WAIS-R Wechsler Adult Intelligence Scale: Revised

WISC-R Wechsler Intelligence Scale for Children: Revised

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25. Heggelund L, Mollnes TE, Ueland T, Christophersen B, Aukrust P, Froland SS. Mannose-bindinglectin in HIV infection: relation to disease progression and highly active antiretroviral therapy. JAcquir Immune Defic Syndr. 2003; 32:354–61. [PubMed: 12640191]

26. Bax WA, Cluysenaer OJ, Bartelink AK, Aerts PC, Ezekowitz RA, van Dijk H. Association offamilial deficiency of mannose-binding lectin and meningococcal disease. Lancet. 1999;354:1094–5. [PubMed: 10509505]

27. Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M. Association of variants of the genefor mannose binding lectin with susceptibility to meningococcal disease. Lancet. 1999; 353:1049–53. [PubMed: 10199352]

28. Lanzrein AS, Jobst KA, Thiel S, Jensenius JC, Sim RB, Perry VH, et al. Mannan-binding lectin inhuman serum, cerebrospinal fluid and brain tissue and its role in Alzheimer’s disease. ClinNeurosci. 1998; 9:1491–5.

29. Verdu P, Barreiro LB, Patin E, Gessain A, Cassar O, Kidd JR, et al. Evolutionary insights into thehigh worldwide prevalence of MBL2 deficiency alleles. Hum Mol Genet. 2006; 15:2650–8.[PubMed: 16885193]

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https://www.researchgate.net/publication/12789979_Association_of_familial_deficiency_of_mannose-binding_lectin_and_meningococcal_disease?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==



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https://www.researchgate.net/publication/8227450_Mannose_binding_lectin_MBL_and_HIV?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==

https://www.researchgate.net/publication/8227450_Mannose_binding_lectin_MBL_and_HIV?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==

https://www.researchgate.net/publication/10595927_Inhibition_of_DC-SIGN-mediated_trans_infection_of_T_cells_by_mannose-binding_lectin?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==

https://www.researchgate.net/publication/10595927_Inhibition_of_DC-SIGN-mediated_trans_infection_of_T_cells_by_mannose-binding_lectin?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==

https://www.researchgate.net/publication/12075368_Mannose-binding_lectin_Structure_function_genetics_and_disease_associations?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==

https://www.researchgate.net/publication/12075368_Mannose-binding_lectin_Structure_function_genetics_and_disease_associations?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==

https://www.researchgate.net/publication/13654027_Mannan-binding_lectin_in_human_serum_cerebrospinal_fluid_and_brain_tissue_and_its_role_in_Alzheimer's_disease?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==



https://www.researchgate.net/publication/6791476_Diversity_of_the_MBL2_Gene_in_Various_Brazilian_Populations_and_the_Case_of_Selection_at_the_Mannose-Binding_Lectin_Locus?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==



https://www.researchgate.net/publication/10853759_Mannose-Binding_Lectin_in_HIV_Infection_Relation_to_Disease_Progression_and_Highly_Active_Antiretroviral_Therapy?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==



https://www.researchgate.net/publication/14193863_Garred_P_et_al_Susceptibility_to_HIV_infection_and_progression_of_AIDS_in_relation_to_variant_alleles_of_mannose-binding_lectin_Lancet_349_239-240?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==



https://www.researchgate.net/publication/238209266_The_Meningococcal_Research_Group_Association_of_variants_of_the_gene_for_mannose-binding_lectin_with_susceptibility_to_meningococcal_disease?el=1_x_8&enrichId=rgreq-e3cb24c58ab40bea96446581360e333e-XXX&enrichSource=Y292ZXJQYWdlOzUyNDk3OTU7QVM6OTg1NjA3MjA3NjkwMzZAMTQwMDUxMDExNTkzOA==



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FIG 1.Association of MBL2 exon 1 genotypes on PFS by age (≥2 vs <2 years).

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FIG 2.Association of MBL2 exon 1 genotypes on CNS PFS by age (≥2 vs <2 years).

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TAB

LE I

Cha

ract

eris

tics o

f chi

ldre

n by

age

gro

ups T

otal

(n =

103

7)≥

2 y

(n =

559

)<2

y (n

= 4

78)

P va

lue

Sex

M

ale

469

(45%

)24

9 (4

5%)

220

(46%

).6

614

Fe

mal

e56

8 (5

5%)

310

(55%

)25

8 (5

4%)

Rac

e/et

hnic

ity

B

lack

625

(60%

)33

2 (5

9%)

293

(61%

).4

025

H

ispa

nic

271

(26%

)15

5 (2

8%)

116

(24%

)

W

hite

141

(14%

)72

(13%

)69

(14%

)

Follo

w-u

p tim

e

<1

2 m

o30

0 (2

9%)

149

(27%

)15

1 (3

2%)

.308

4

≥

12-2

3 m

o45

0 (4

3%)

254

(45%

)19

6 (4

1%)

>2

3-35

mo

197

(19%

)10

9 (1

9%)

88 (1

8%)

>3

5 m

o90

(9%

)47

(8%

)43

(9%

)

PFS

even

ts

N

o81

1 (7

8%)

484

(87%

)32

7 (6

8%)

<.00

01

Y

es22

6 (2

2%)

75 (1

3%)

151

(32%

)

Dis

ease

pro

gres

sion

end

poi

nt

N

o ev

ent

811

(78%

)48

4 (8

7%)

327

(68%

)

de

ath

25 (2

%)

1 (0

%)

24 (5

%)

≥

2 O

ppor

tuni

stic

infe

ctio

ns7

(1%

)4

(1%

)3

(1%

)

W

eigh

t gro

wth

failu

re75

(7%

)41

(7%

)34

(7%

)

M

alig

nanc

y1

(0%

)0

(0%

)1

(0%

)

C

DC

clin

ical

dis

ease

cat

egor

y C

12 (1

%)

4 (1

%)

8 (2

%)

A

ll C

NS

dise

ase

prog

ress

ion

even

ts:

106

(10%

)25

(4%

)81

(17%

)

a. D

eter

iora

tion

of b

rain

gro

wth

65 (6

%)

21 (4

%)

44 (9

%)

b. D

eter

iora

tion

of n

euro

cogn

itive

func

tion

12 (1

%)

1 (0

%)

11 (2

%)

c. D

eter

iora

tion

of n

euro

logi

c st

atus

29 (3

%)

3 (1

%)

26 (5

%)

Bas

elin

e ch

arac

teris

tics b

y ag

e gr

oups

B

asel

ine

CD

4 (%

)

N1,

029

557

472

<.00

1


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Tot

al (n

= 1

037)

≥2

y (n

= 5

59)

<2 y

(n =

478

)P

valu

e

Med

ian

2422

.45

26.9

8

B

asel

ine

CD

4 co

unt/m

m3

N1,

029

557

472

NA

*

Med

ian

774.

9859

612

69.5

0

B

asel

ine

log 1

0 RN

A c

opie

s/m

L

N86

146

739

4<.

001

Med

ian

5.12

4.73

5.64

B

asel

ine

cogn

itive

scor

e

N97

952

545

4.2

74

Med

ian

8383

83

B

asel

ine

WA

Z sc

ore

N10

3755

947

8<.

001

Med

ian

-0.6

9-0

.29

-1.1

1

* Not

cal

cula

ted

beca

use

youn

ger c

hild

ren

gene

rally

hav

e hi

gher

abs

olut

e C

D4

coun

ts th

an o

lder

chi

ldre

n.


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TABLE II

Association of MBL2 genotypes on progression-free survival in children: Whole cohort

MBL2 genotypes compared RH (95% CI), P value

O/O vs A/O* 1.45 (0.78-2.72), .24

Adjusted† 1.90 (0.94-3.85), .07

Adjusted‡ 1.49 (0.78-2.84), .22

Adjusted§ 1.46 (0.77-2.76), .25

O/O vs A/A* 1.29 (0.95-1.76), .10

Adjusted† 1.37 (0.97-1.94), .07

Adjusted‡ 1.22 (0.89-1.67), .21

Adjusted§ 1.34 (0.97-1.84), .078

O/O vs A/O+A/A* 1.57 (0.86-2.88), .14

Adjusted† 1.91 (0.97-3.76), .06

Adjusted‡ 1.49 (0.80-2.75), .20

Adjusted§ 1.62 (0.87-3.00), .13

*Unadjusted.

†Adjusted for CD4+ lymphocyte count, HIV-1 RNA, treatments, race, and sex.

‡Adjusted for CCR5-wt/Δ32, -59029-G/A, CX3CR1-249-V/I, -280-T/M, and SDF-1-180-G/A.

§Adjusted for MBL2-H/L, MBL2-P/Q, and MBL2-X/Y.


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TABLE III

Association of MBL2 genotypes on CNS progression-free survival in children: Whole cohort

MBL2 genotypes compared RH (95% CI), P value

O/O vs A/O* 2.24 (1.00-5.01), .045

Adjusted† 2.77 (1.13-6.79), .03

Adjusted‡ 2.51 (1.09-5.81), .03

Adjusted§ 2.37 (1.02-5.50), .04

O/O vs A/A* 1.46 (0.98-2.16), .054

Adjusted† 1.63 (1.06-2.51), .03

Adjusted‡ 1.38 (0.92-2.06), .12

Adjusted§ 1.58 (1.04-2.41), .032

O/O vs A/O+A/A* 2.15 (1.00-4.64), .04

Adjusted† 2.74 (1.19-6.33), .02

Adjusted‡ 2.04 (0.94-4.46), .07

Adjusted§ 2.44 (1.10-5.39), .027

*Unadjusted.





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TABLE IV

Association of MBL2 genotypes on progression-free survival in children: Age (≥2 vs <2 y)

MBL2 genotypes Compared Age ≥2 y: RH (95% CI), P value Age <2 y: RH (95% CI), P value

O/O vs A/O* 0.83 (0.25-2.70), .75 2.28 (1.09, 4.79) p=0.029

Adjusted† 3.73 (0.71-19.6), .12 2.21 (0.94-5.15), .067

Adjusted‡ 0.91 (0.26-3.16), .88 2.07 (0.95-4.49), .066

Adjusted§ 0.88 (0.26-2.95), .84 2.27 (1.05-4.88), .036

O/O vs A/A* 1.05 (0.58-1.90), .87 1.54 (1.07-2.22), .02

Adjusted† 1.00 (0.46-2.17), .99 1.38 (0.92-2.08), .12

Adjusted‡ 1.02 (0.56-1.88), .94 1.53 (1.04-2.24), .03

Adjusted§ 1.11 (0.60-2.03), .74 1.53 (1.04-2.25), .029

O/O vs A/O+A/A* 0.97 (0.30-3.07), .95 2.33 (1.14-4.76), .02

Adjusted† 1.55 (0.35-6.83), .56 2.14 (0.98-4.69), .058

Adjusted‡ 0.87 (0.27-2.87), .82 2.19 (1.05-4.55), .036

Adjusted§ 1.04 (0.32-3.35), .95 2.33 (1.12-4.83), .024

*Unadjusted.





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TABLE V

Association of MBL2 genotypes on CNS progression-free survival in children: Age (≥2 vs <2 y)

MBL2 genotypes compared Age ≥2 y: RH (95% CI), P value Age <2 y: RH (95% CI), P value

O/O vs A/O* 1.93 (0.41-9.01), .40 2.78 (1.07-7.21), .035

Adjusted† 4.72 (0.43-52.1), .20 3.56 (1.24-10.3), .019

Adjusted‡ 3.71 (0.67-20.4),.13 3.08 (1.11-8.54), .031

Adjusted§ 2.25 (0.44-11.6), .33 3.11 (1.14-8.47), .027

O/O vs A/A* 1.33 (0.63-2.81), .45 1.69 (1.06-2.69), .027

Adjusted† 1.00 (0.35-2.86), 1.00 1.75 (1.06-2.90), .028

Adjusted‡ 1.46 (0.68-3.13), .33 1.65 (1.01-2.69), .045

Adjusted§ 1.85 (0.82-4.15), .14 1.67 (1.02-2.73), .042

O/O vs A/O+A/A* 1.78 (0.42-7.62), .44 2.82 (1.14-7.00), .03

Adjusted† 1.30 (0.17-10.28), .80 3.38 (1.31-8.74), .012

Adjusted‡ 2.25 (0.50-10.1), .29 2.81 (1.10-7.16), .031

Adjusted§ 2.64 (0.58-12.0), .21 3.05 (1.19-7.77), .020

*Unadjusted.





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TAB

LE E

1

Dis

tribu

tion

of M

BL2

geno

type

s and

hap

loty

pes b

y ra

ce/e

thni

city

Rac

e/et

hnic

ity

Tot

al (n

= 1

037)

Bla

ck (n

= 6

25)

His

pani

c (n

= 2

71)

Whi

te (n

= 1

41)

P va

lue

Exon

1 g

enot

ype

A

/A57

0 (5

5%)

335

(54%

)14

8 (5

5%)

87 (6

2%)

<.00

01

A

/B13

7 (1

3%)

45 (7

%)

62 (2

3%)

30 (2

1%)

A

/C22

3 (2

2%)

182

(29%

)33

(12%

)8

(6%

)

A

/D45

(4%

)18

(3%

)16

(6%

)11

(8%

)

O

/O62

(6%

)45

(7%

)12

(4%

)5

(4%

)

Prom

oter

regi

on g

enot

ype

Y

/Y76

2 (7

3%)

472

(76%

)19

2 (7

1%)

98 (7

0%)

.447

4

X

/Y24

8 (2

4%)

139

(22%

)71

(26%

)38

(27%

)

X

/X27

(3%

)14

(2%

)8

(3%

)5

(4%

)

Prom

oter

regi

on g

enot

ype

H

/H60

(6%

)20

(3%

)24

(9%

)16

(11%

)<.

0001

H

/L35

9 (3

5%)

171

(27%

)12

4 (4

6%)

64 (4

5%)

L

/L61

8 (6

0%)

434

(69%

)12

3 (4

5%)

61 (4

3%)

Unt

rans

late

d re

gion

gen

otyp

e

P

/P36

2 (3

5%)

159

(25%

)13

9 (5

1%)

64 (4

5%)

<.00

01

P

/Q49

2 (4

7%)

317

(51%

)11

0 (4

1%)

65 (4

6%)

Q

/Q18

3 (1

8%)

149

(24%

)22

(8%

)12

(9%

)

Hap

loty

pes

H

YPA

74 (7

%)

25 (4

%)

30 (1

1%)

19 (1

3%)

<.00

01

H

XPA

328

(32%

)15

6 (2

5%)

112

(41%

)60

(43%

)

L

YPA

199

(19%

)12

7 (2

0%)

48 (1

8%)

24 (1

7%)

L

XPA

221

(21%

)15

3 (2

4%)

47 (1

7%)

21 (1

5%)

O

ther

s21

5 (2

1%)

164

(26%

)34

(13%

)17

(12%

)


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TAB

LE E

2

Dis

tribu

tion

of M

BL2

geno

type

s and

hap

loty

pes b

y ag

e

Age

gro

ups

Tot

al (n

= 1

037)

≥2

y (n

= 5

59)

<2 y

(n =

478

)P

valu

e

Exon

1 g

enot

ype

O

/O34

(3%

)19

(3%

)15

(3%

).9

650

A

/O40

5 (3

9%)

219

(39%

)18

6 (3

9%)

A

/A59

8 (5

8%)

321

(57%

)27

7 (5

8%)

Prom

oter

regi

on g

enot

ype

Y

/Y76

2 (7

3%)

416

(74%

)34

6 (7

2%)

.039

4

X

/Y24

8 (2

4%)

135

(24%

)11

3 (2

4%)

X

/X27

(3%

)8

(1%

)19

(4%

)

Prom

oter

regi

on g

enot

ype

H

/H60

(6%

)35

(6%

)25

(5%

).6

483

H

/L35

9 (3

5%)

188

(34%

)17

1 (3

6%)

L

/L61

8 (6

0%)

336

(60%

)28

2 (5

9%)

Unt

rans

late

d re

gion

gen

otyp

e

P

/P36

2 (3

5%)

184

(33%

)17

8 (3

7%)

0.25

01

P

/Q49

2 (4

7%)

278

(50%

)21

4 (4

5%)

Q

/Q18

3 (1

8%)

97 (1

7%)

86 (1

8%)


An age-dependent association of mannose-binding lectin-2 genetic variants on HIV1–related disease...

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Transcript of An age-dependent association of mannose-binding lectin-2 genetic variants on HIV1–related disease...